The present invention relates to pharmaceutical compositions useful as carriers to transport biologically active materials in general. More specifically, it relates to novel phospholipid-drug formulations having improved bio-availability, less variability, low toxicity and ease of use either as liquids or as unit dosage forms filled into gelatin capsules or the like.
The Problem of Bioavailability
The ultimate goal in drug delivery is clinical efficacy, which can only be achieved when an optimal amount of drug is available in the systemic circulation, the target organ or tissue. In the specific case of oral delivery, it is a requisite for the drug to be adequately absorbed from the gastrointestinal (GI) tract to give good and consistent bioavailability. Many biologically active compounds are xe2x80x98problemxe2x80x99 drugs that have poor and variable oral bioavailability, resulting in lack of efficacy. In many cases this is due to physical factors such as high molecular weight, poor aqueous solubility, or biological factors manifested in low membrane permeability.
Generally, drug absorption and the membrane permeability of drugs are strongly influenced by lipophilicity although polarity and H-bonding of the molecule may also play their part. The more lipophilic the drug, the more easily it partitions into biological membranes. The presence of lipophilic groups, however, leads to marked decreases in aqueous solubility and hence drug concentration at membrane surfaces. This, in turn, leads to lowered uptake and bioavailability. It is generally accepted that lipophilic compounds with molecular weights above about 600 have poor aqueous solubility.
Modern drug discovery programs based on combinational chemistry and high through-put screening methods to identify active compounds are biased towards the selection of lipophilic entities because of the non-aqueous solvents used to solubilise the compounds for screening. It has been reported that about 40% of active compounds coming out of drug discovery programs are lipophilic actives that have poor bioavailability.
Poor absorption is not exclusive to lipophilic compounds. Some hydrophilic compounds e.g. peptides may also have low membrane permeability due to their polar nature and their large molecular size. There is as yet an unfulfilled requirement for safe and effective formulation approaches which improve the bioavailability and decrease variable absorption of poorly absorbed compounds without structural modification of the active molecule. This applies to both lipophilic and hydrophilic compounds.
Bioavailability of Macrolides
Macrolides such as tacrolimus, rapamycin, cyclosporin and their derivatives are examples of fungal metabolites that have poor bioavailability due to erratic and unpredictable uptake from the gastro-intestinal tract. For example, the oral bioavailability of tacrolimus is reported to vary between 5% to 67%. Furthermore, the bioavailability of sub-optimally formulated cyclosporin A may be greatly influenced by the presence of food, increasing from about 30% to 60%. Rapamycin is also a xe2x80x98problemxe2x80x99 drug which is difficult to formulate in oral dosage forms because of poor bioavailability. As a class, these compounds have a variety of pharmacological properties, of which immunosuppression is presently the most important clinically. Other clinical applications that are currently under investigation include modification of multi drug resistance, anti-viral and anti-fungal properties. The most widely used drug for preventing xenograft rejection is cyclosporin A.
Cyclosporins are hydrophobic neutral cyclic peptides with essentially similar chemical and physical properties. Cyclosporin A (cyA) is representative and is the best known example. CyA is widely used in organ transplants to prevent rejection and as an immunosuppressive agent in the treatment of systemic and local auto-immune disorders in which T cells play a major role. CyA has also been used to treat chronic conditions such as rheumatoid arthritis, asthma and non-malignant skin disorders. A cyclosporin derivative eg. PSC 833 is known to modify multi-drug resistance with cytotoxic drugs.
There are two commercially available forms of cyA called Sandimmune and Neoral. Sandimmune (see Swiss Patent 641356) is a solution of cyA in olive oil and ethanol which is emulsified in water using a polyethoxylated oleic surfactant. It suffers from the disadvantage that absorption is incomplete and variable. Neoral can give consistent absorption but relies on potentially harmful synthetic surfactants to form micro emulsions which require a lipophilic phase.
Phospholipids and Their Use
The use of phospholipids in the form of liposomes as vehicles of drug delivery is well established both in the patent and scientific literature. The limitations of the use of pre-formed liposome preparations has been extensively reviewed (see EP-A-0158441) and need not be recapitulated here.
Many of these limitations can be overcome by the use of phospholipid mixtures in a hydrophilic medium, described as pro-liposome compositions to carry active compounds as first disclosed in EP 0158441. These latter compositions comprise blends of bilayer forming diacyl phospholipids, which on dilution with aqueous fluids formed closed vesicular structures with high entrapment of a biologically active compound. WO 88/06438 discloses similar compositions to the above, and claims desalted charged diacyl lipids in a non aqueous water miscible medium. EP-A-0030577 discloses a method of preparing liposomes using mixtures of diacyl phospholipids dissolved or dispersed in a non-volatile hydrophilic medium.
Following these disclosures, there have been many examples which rely essentially on diacyl phospholipids, or lecithin, to improve the delivery of active compounds. Thus EP 0648494 A1 mentions the use of lecithin solutions as a major component, to deliver rapamycin and its derivatives. Similarly, WO 98/40094 describes binary pharmaceutical compositions of a cyclosporin compound, where lecithin or diacyl phospholipids is an auxiliary component.
Departing from the reliance on diacyl phospholipids to carry biologically active compounds, WO 98/58629 discloses substantially homogenous compositions for human administration comprising a biologically active lipophilic compound dissolved in or associated with at least one micelle-forming lipid e.g. monoacyl phosphatidylcholine, or blends of monoacyl phosphatidylcholine with diacyl phosphatidylcholine. The compositions were shown to be surprisingly effective in solubilising and improving the bioavailability of compounds that have poor or variable absorption.
EP 0256090 discloses the use of a specific monoacyl phospholipid species, namely monoacyl phosphatidyl-ethanolamine and a hydrophobic compound, in the form of a micellar suspension at a pH between 8.2 to 14, for intravenous and other injectable purposes.
The use of dilute solutions containing 0.625% w/v MAPC which has 10 or more carbon groups in their fatty acid chain for enhancing the nasal delivery of insulin has also been reported in Pharm Res., Vol 11, No. 11, 1994 p 1623-1630.
An object of this invention is to improve the bioavailability and consistency in absorption of either lipophilic or hydrophilic compounds.
Another object of the invention is to reduce variable absorption of lipophilic and hydrophilic compounds.
A further object of this invention is to improve the bioavailability of active compounds in liquid, semi-solid or gel-like formulations.
A further object of this invention is to provide an efficient, effective and non-toxic carrier for compounds that have poor bioavailability eg. cyA where poor solubility would undoubtedly be a factor which prevents the compound being transported in molecular dispersion to the absorption surfaces in the GI tract.
The present invention concerns a further development of the compositions disclosed in co-pending patent application WO 98/58629, in a liquid form. The compositions in this invention can mimic partially digested food mixtures, allowing for higher absorption of xe2x80x98problemxe2x80x99 compounds compared to compositions that only rely on diacyl phospholipids.
One feature of the invention is that the present formulations contain at least one micelle forming monoacyl membrane lipid either alone or preferably in combination with one or more bilayer-forming diacyl membrane lipids. The compositions are characterised by the presence of an effective amount of the monoacyl component dissolved or dispersed in a hydrophilic medium.
The invention provides a composition for delivering at least one biologically active compound to a living organism, said composition comprising at least one micelle-forming membrane lipid characterised in that the composition contains at least one hydrophilic material in an amount effective to render the composition into a liquid, gel or semi-solid which has the property of yielding dispersed lipid aggregates upon contact or further dilution with an aqueous medium.
The invention further provides a liquid pharmaceutical composition comprising:
(a) a mixture of membrane lipids which comprises a micelle-forming lipid and preferably a bilayer-forming lipid;
(b) at least one hydrophilic medium to mobilise the lipids; and optionally
(c) at least one biologically active compound.
The invention further provides a liquid pharmaceutical composition comprising:
(a) a mixture of membrane lipids which comprises firstly a micelle-forming lipid and secondly a bilayer-forming lipid;
(b) water in an amount which is effective to hydrate the lipid mixture; and
(c) at least one biologically active compound.
The invention will be further discussed mainly in terms of oral applications. The formulation principles involved, however, are of general applicability and it should be appreciated that the compositions described are equally suitable for a wide range of other applications.
The above compositions may be formulated so as to be flowable at room or alternatively at elevated temperature for filling into gelatin capsules. The composition may also optionally contain polymers which influence the dispersibility characteristics of the composition on exposure to water or aqueous solutions. Other excipients and stabilisers such as organic thickeners, antioxidants, flavourings, anti-microbial agents, buffering agents, colouring agents and sweetening agents may also be included. The inclusion of surfactants and small amounts of oils as minor components is not excluded. Similarly, membrane stabilisers such as cholesterol, dicetyl phosphate, stearyl amine and other charged amphipathic compounds may be added to the compositions to improve stability.
The formulations may exhibit remarkably good storage stability. They are normally liquid or gel-like presentations at room temperature and may be used as such or filled into unit dosage forms e.g. soft gelatin capsules. Alternatively, the compositions are fluids at elevated temperatures that harden on cooling to room temperature. Such formulations are suitable for filling into hard gelatin capsules or the like as a liquid at temperatures not exceeding about 70xc2x0 C., solidifying to a plug inside the shell at room temperature.
Lipophilic drugs such as cyA and other compounds can be solubilised in solutions of at least one monoacyl lipid (e.g. MAPC), preferably with diacyl lipids (e.g.PC) in a hydrophilic medium. The reason for the use of such mixtures is three-fold. Firstly, such mixtures can solubilise much higher amounts of lipophilic bioactive compounds such as cyA, than diacyl lipids alone. Secondly, the presence of the monoacyl lipid influences the internal structure and improves the stability of these mixtures, particularly in the presence of water. Thirdly, the bioavailability of cyA may be greatly improved because of better retention at the absorption surfaces and enhanced mucosal penetration due to the presence of MAPC. However, it must not be construed that these are the only reasons.
On contact with water or other aqueous medium, or upon dilution in such media, the compositions have the potential to hydrate. Depending on the precise composition and desired application, the preparations may remain substantially intact in the form of a bolus or disperse rapidly, or more gradually, to form lipid aggregates. The term lipid aggregates is used here to describe a combination of vesicular and non-vesicular structures e.g. liposomes, and various species of micelles and mixed micelles.
Dispersibility and the different types of aggregate structures formed depend on a number of factors e.g. the relative amount and the type of lipid and hydrophilic medium, pH, viscosity and optionally, the presence of other components e.g. polymers and surfactants.